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PubMed1994

Effect of diuretics on morbidity and mortality in the treatment of hypertension.

Diuretic-based hypertension treatment trials have universally demonstrated a reduction in cardiovascular morbidity and mortality in treated compared with placebo or control subjects. Progression to more severe hypertension has been reduced together with reversal of left ventricular hypertrophy if present and prevention of congestive heart failure. The incidence of fatal and non-fatal strokes as well as coronary heart disease events have both been significantly reduced by diuretic-based treatment. Speculation that diuretic-induced adverse effects on lipid and glucose metabolism have negated the beneficial effects of blood pressure lowering has not been substantiated. Diuretics remain one of the preferred initial therapies in the management of hypertension.

Cerebrovascular Disorders↗
PubMed1994

Metabolic effects of diuretics.

Hypokalaemia, hyperuricaemia, hypomagnesaemia and alterations to lipid and glucose metabolism undoubtedly occur with loop and thiazide diuretic treatment. Many of the metabolic effects induced by thiazide diuretics, however, can be limited by the use of low doses. Apart from precipitation of gout and worsening control of diabetes the clinical importance of these changes is slight. In hypertensive patients treated with diuretics, long-term outcome trials have shown significant benefit in terms of reduction in stroke and coronary events. Diuretics should therefore remain first-line treatment for all patients with heart failure, and in patients with hypertension except those with diabetes or gout.

Calcium↗
PubMed1994

Diuretic resistance: mechanisms and therapeutic strategies.

The mechanism(s) responsible for diuretic resistance differ in different clinical conditions. Renal insufficiency is a prototype of a pharmacokinetic mechanism wherein the disease causes decreased delivery of diuretic to its urinary site of action. Hepatic cirrhosis, on the other hand, is a prototype of a pharmacodynamic mechanism wherein normal amounts of diuretic reach the site of action but nephron response is subnormal. The mechanism of this effect is unknown. In congestive heart failure and in nephrotic syndrome, both pharmacokinetic and pharmacodynamic mechanisms occur. The different mechanisms of diuretic resistance in these various diseases dictate specific therapeutic strategies for each clinical condition.

Diuretics↗
PubMed1991

Stasis oedema in the elderly: are diuretics necessary?

Diuretic therapy was discontinued in 15 elderly patients. None of these patients had evidence of uncontrolled cardiac failure or hypertension, and they all had received diuretics long-term. Two patients required resumption of diuretics due to the development of cardiac failure or severe leg oedema. In the remaining 13 patients, mean leg volume increased by 8.2%. Discontinuation of diuretic therapy in elderly patients is associated with a small but significant worsening of lower limb oedema.

Aged↗
PubMed1989

Diuretic agents versus beta-blockers. Comparison of effects on mortality, stroke, and coronary events.

Three recently concluded large randomized clinical trials have compared the preventive effects of diuretic agents and beta-blockers in the treatment of approximately 22,000 subjects with hypertension. In the Medical Research Council trial, bendrofluazide (10 mg daily) was compared with a dose of propranolol (as much as 240 mg daily), a nonselective beta-blocker without intrinsic sympathomimetic activity. Two selective beta-blockers, atenolol (100 mg daily) and metoprolol (200 mg daily), were compared with bendrofluazide (5-10 mg daily) and hydrochlorothiazide (50-100 mg daily) in the Heart Attack Primary Prevention in Hypertension trial. In the International Prospective Primary Prevention Study in Hypertension, 160 mg of slow-release oxprenolol, a beta-blocker with intrinsic sympathomimetic activity, was compared with a diuretic-based regimen not containing beta-blockers. In each trial, similar reductions in mean diastolic blood pressure were achieved with diuretic and beta-blocker treatment that lasted for several years. All-cause mortality and fatal and nonfatal stroke and coronary event rates were also similar in the treatment groups. Thus, it appears that beta-blockers are as effective as diuretic agents in improving survival and in preventing major morbid events. Regarding cigarette smoking and stroke incidence, observations based on post hoc subgroup analyses of the Medical Research Council trial were not supported by subgroup findings in the Heart Attack Primary Prevention in Hypertension and the International Prospective Primary Prevention Study in Hypertension trials, and these observations should not form the basis for any treatment recommendations.

Adrenergic beta-Antagonists↗
PubMed1991

Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study.

The present study in hypertensive men (40-64 years old) with untreated diastolic blood pressure above 100 mm Hg was aimed at investigating whether metoprolol (n = 1,609) given as initial treatment would lower the risk for coronary events (sudden death and myocardial infarction) more effectively than thiazide diuretics (n = 1,625). A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension (HAPPHY) study. The HAPPHY study was a pooling of the effect of different beta-blockers, mainly metoprolol and atenolol, in which no favorable effect in relative risk was observed for atenolol as compared with diuretics. In the present study, 255 patients suffered definite coronary events during follow-up; 25% of these events were fatal, 39% were acute myocardial infarctions, and 36% were silent myocardial infarctions. The risk for coronary events was significantly lower in patients on metoprolol than in patients on diuretics (111 versus 144 cases, p = 0.001, corresponding to 14.3 versus 18.8 cases/1,000 patient years and a relative risk of 0.76 at the end of the trial; 95% confidence interval 0.58-0.98). This difference in risk has potentially important implications for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events. Because a placebo group, for ethical reasons, could not be included, relative risk can only be expressed in relation to diuretics. There was no difference between the two treatment groups in baseline characteristics, blood pressure during follow-up, or stroke rates. Thus, the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control. However, present data might suggest that different beta-blockers may have different efficacy in preventing coronary events. The reasons for this possibility are as yet unknown.

Adult↗
PubMed2000

Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program.

The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium <3.5 mmol/L compared with 1% of the participants randomized to placebo (P<0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (P<0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.

Aged↗
PubMed1991

Loop diuretics inhibit cholinergic and noncholinergic nerves in guinea pig airways.

Furosemide, a loop diuretic, is known to inhibit the response to a variety of indirect bronchial challenges in humans but does not inhibit bronchoconstriction induced by inhaled methacholine or histamine. We have investigated the effects of the two loop diuretics, furosemide (10(-6) to 10(-3) M) and bumetanide (10(-7) to 10(-4) M), on airway smooth muscle contraction in vitro induced by electrical field stimulation (EFS), or exogenously applied acetylcholine (ACh) or substance P (SP) in guinea pig tracheal and bronchial smooth muscle strips pretreated with indomethacin (10(-5) M) and propranolol (10(-6) M). Both furosemide and bumetanide caused a concentration-dependent inhibition of cholinergically mediated neural contraction in the trachea. The effect of furosemide was not influenced by the presence of airway epithelium. Furthermore, both furosemide and bumetanide inhibited in a concentration-dependent fashion nonadrenergic, noncholinergic (NANC) contraction induced by electrical field stimulation of bronchi pretreated with atropine (10(-5) M). Neither drug at the highest concentration inhibited the responses to exogenous acetylcholine (10(-8) to 10(-2) M) or substance P (10(-9) to 10(-5) M). Thus loop diuretics inhibit the neurally induced contraction of guinea pig airways without a direct effect on airway smooth muscle. We conclude that loop diuretics inhibit both cholinergic and excitatory NANC neurotransmission in guinea pig airways and that this effect may be related to their inhibitory effects on the sodium-potassium-chloride cotransporter.

Animals↗
PubMed1980

Diuretics stimulate H+ secretion in turtle urinary bladder.

The effect of various diuretics on H+ secretion was studied in the isolated short-circuited urinary bladder of the turtle. Mucosal (urinary) chlorothiazide stimulated H+ secretion promptly, from 1.33 +/- 0.24 to 3.03 +/- 0.25 mueq/h (P less than 0.001). The effect was rapidly reversible upon washout of the drug, H+ returning to control levels, 1.37 +/- 0.26 mueq/h (P less than 0.001). Similar effects were observed with mucosal hydrochlorothiazide and mucosal ethacrynic acid/cysteine. Stimulation of H+ secretion occurred in the presence or the absence of exogenous CO2, in the presence or absence of mucosal Na+ and during inhibition of Na+ transport by ouabain. There was no stimulation of H+ secretion by uncomplexed ethacrynic acid or by mucosal furosemide. The nondiuretic sulfonamide, sulfasoxizole, and the nonsulfonamide buffer, borate, had no effect on H+ SECRETION. These observations indicate that the stimulatory effect of diuretics on H+ secretion is not related to active sodium transport, transepithelial electrical potential, or the buffering capacity of the drugs. Since the transepithelial pH gradient at which active H+ secretion was abolished was identical for chlorothiazide-treated tissues (2.68 pH U) as for control tissues (2.65 pH U, NS), the data suggest that the protonmotive force of the H+ pump was unaffected by the diuretic. This observation, plus the rapid onset and reversibility of the drugs, is consistent with an effect on the mucosal membrane to increase H+ conductance (K). The findings raise the possibility that direct enhancement of renal H+ secretion may play a role in the metabolic alkalosis induced by some diuretics.

Animals↗
PubMed1985

Serum potassium testing in diuretic-treated outpatients. A multivariate approach.

We evaluated risk factors for abnormal serum potassium (K+) concentrations in 5817 outpatients on chronic diuretic therapy. Hypokalemia (K+ less than 3.5 meq/L) occurred in 18.8 percent at the last clinic measurement. Hyperkalemia (K+ greater than 5.5) was rare (0.5%) and was even less common in those also taking KCl or a K+ sparing drug (0.2%). Hypokalemic patients were younger, healthier, more often hypertensive, more commonly taking a thiazide diuretic, and more likely to have been hypokalemic in the past. Hyperkalemic patients were older, more often suffering from heart or renal failure, and more commonly taking furosemide. Logistic regression analysis yielded eight variables that contributed significantly to the prediction of hypokalemia: mean and most recent serum K+, thiazide use, the use and duration of use of potassium-sparing diuretics, age, and most recent serum sodium and bicarbonate determinations. The regression equation allowed us to identify a group of patients (63% of the total) at low risk for hypokalemia (K+ less than 3.5 in 9.4%; K+ less than 3.0 in 0.5%) and another group (37% of the total) at high risk for hypokalemia (K+ less than 3.5 in 35%; K+ less than 3.0 in 5%). Information about the risk of hypokalemia can be used to decide when to measure serum potassium concentration in individual diuretic-treated outpatients.

Benzothiadiazines↗
PubMed1986

Positive synergism between diuretics and methylprednisolone following acute myocardial infarction.

In studies of patients with cardiac failure following an acute myocardial infarction, 1114 patients were followed for 7-day mortality. In the 45% of patients receiving diuretics on day 1, the death rate was twice that of patients not receiving diuretics. In patients treated 6 to 12 hours following the onset of chest pain, mortality was 2.8 times that of patients treated within 6 hours of the onset of chest pain. Randomization to methylprednisolone sodium succinate (MPSS, Solu-Medrol Sterile Powder, The Upjohn Company) did not improve the low mortality rates of those patients who did not need diuretics nor who were treated early. However, patients who were treated late and who needed diuretics and who were randomized to MPSS had a death rate half that of those who received placebo.

Clinical Trials as Topic↗
PubMed1995

Torsemide: a pyridine-sulfonylurea loop diuretic.

OBJECTIVE: To review the clinical pharmacology of torsemide and to compare it with currently available loop diuretics, particularly furosemide. DATA SOURCES: An English-language MEDLINE search, 1985 to October 1994, was used to identify pertinent literature, including review articles. DATA EXTRACTION: Data from scientific literature were extracted, evaluated, and summarized for presentation. Pivotal and representative studies are discussed relating to the pharmacology, pharmacokinetics, and use of torsemide in patients with congestive heart failure, renal disease, hepatic disease, and hypertension. DATA SYNTHESIS: Torsemide is a loop diuretic of the pyridine-sulfonylurea class. The bioavailability of torsemide is approximately 80%, with little first-pass metabolism, and torsemide can be given without regard to meals. The serum concentration reaches its peak within 1 hour after oral administration and diuresis lasts approximately 6-8 hours. Torsemide is eliminated both hepatically (80%) and renally (20%) as unchanged drug with an elimination half-life of about 3.5 hours. Because of the high bioavailability, oral and intravenous doses are therapeutically equivalent. Torsemide, and other loop diuretics such as furosemide, are indicated for the treatment of edema associated with congestive heart failure, renal disease, and hepatic disease. They also are indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. Depending on the indication, the recommended initial adult dosage of torsemide is between 5 and 20 mg once daily orally or intravenously. Special dosage adjustments in the elderly are not necessary. CONCLUSIONS: Torsemide is a loop diuretic similar to furosemide, with similar indications. Torsemide is characterized by good bioavailability and once-daily dosing and, compared with furosemide, provides generally equivalent therapeutic efficacy.

Clinical Trials as Topic↗
PubMed1985

Cholesterol distribution in cells of the stria vascularis of the mammalian cochlea and some effects of ototoxic diuretics.

The distribution of cholesterol in cells of the stria vascularis of guinea pigs and gerbils has been investigated at the ultrastructural level by incubation of tissue in filipin, followed by freeze-fracture. Verification of results has been sought by using tomatin. It is shown that in the cell body region of the marginal cells, the apical and lateral membranes reacted intensely with both agents, but the membranes of the basal processes of the marginal cells did not respond significantly to either filipin or tomatin. On basal cell membranes, filipin-cholesterol complexes were present at a high density, even within the strands of the tight-junctional network of these cells and occasionally within the gap-junctional areas also. Complexes were present on intermediate cell membranes at a lower density than on other plasma membranes that showed a positive response. Tissue from animals that had received an ototoxic diuretic, either ethacrynic acid or furosemide, was characterized by the appearance of membrane regions with closely clustered filipin complexes, suggesting some change in cell membrane structure. At an early stage following diuretic administration, such clusters were particularly noticeable on the membranes of intermediate cells. As intercellular spaces enlarged in response to the effects of diuretics, vesicles released into the extracellular spaces appeared to be cholesterol-enriched. The results are discussed in relation to known features of the structure and function of cells in the normal stria vascularis and of the changes that follow from acute diuretic ototoxicity.

Animals↗
PubMed1980

Binding of several loop diuretics to serum albumin and human serum from patients with renal failure and liver disease.

The binding of the new diuretic piretanide and two other diuretics (furosemide and bumetanide) to serum proteins (especially albumin) was studied using the in vitro equilibrium dialysis method. Piretanide and bumetanide, similar to each other in chemical structure, were almost equal in the binding constant to purified albumin, while the binding constant of furosemide was greater than that of the other two diuretics. The binding of these loop diuretics in the dilutions of the sera from healthy adults and patients with renal failure or liver disease was also studied by the same method. Protein binding of the drugs was markedly reduced in patients with renal failure. The cause could only partly be explained by some structural changes in the serum albumin molecules of these patients and influences of endogeneous substances present in serum.

Adult↗
PubMed1991

Aryloxy acetic acid diuretics with uricosuric activity. I. Polycyclic aryloxy acetic acids.

In order to obtain lead compounds for uricosuric diuretics, various polycyclic aryloxy acetic acids [isoindole derivative (7), quinazoline derivative (15), benzopyran derivative (20), xanthone derivative (24), benzofuran derivative (30) and indene derivative (36)] were prepared. These compounds were evaluated for diuretic activity in rats, uricosuric activity in rats and antihypertensive activity in 11-deoxycorticosterone acetate (DOCA)/salt hypertensive rats. Among the compounds, 20 showed potent diuretic, uricosuric and moderate antihypertensive activities. Therefore, we selected 20 as a lead compound for development of new uricosuric diuretics.

Acetates↗
PubMed2005

Influence of diuretic-induced dehydration on competitive sprint and power performance.

UNLABELLED: Diuretic-induced dehydration impairs prolonged running performance (> 1500 m). Sprinting performance may suffer by similar mechanisms (i.e., altered cardiovascular strain, heat storage, and metabolism) or may improve because of reduced mass to accelerate and carry. PURPOSE: To examine sprint and power performance after diuretic-induced dehydration. METHODS: After six sprint practice sessions, nine male former sprinters (mean +/- SD; age, 21 +/- 2 yr; body mass (BM), 80.0 +/- 5.2 kg; height, 1.78 +/- 0.08 m; body fat, 14 +/- 4%) participated in a 50-m race, a 200-m race, a 400-m race, and a vertical jump on an indoor synthetic track, once when dehydrated (40-mg furosemide; DD) and once with no diuretic (CON) using a counter-balanced crossover design. Plasma volume change (%deltaPV), heart rate (HR), blood pressure, rectal temperature, serum electrolytes, plasma lactate, plasma glucose, rating of perceived exertion, thirst, and thermal sensations were measured before and after each race. RESULTS: Sprint times (DD vs CON) for the 50 m (6.72 +/- 0.28 vs 6.73 +/- 0.29 s), 200 m (25.95 +/- 1.20 vs 26.21 +/- 1.42 s), and 400 m (59.01 +/- 4.26 vs 58.68 +/- 3.68 s) were similar for both conditions, as was vertical jump height (0.67 +/- 0.10 vs 0.66 +/- 0.11 m). This occurred despite losing 2.2 +/- 0.4% BM and 7.3 +/- 6.7%deltaPV (50/200 m) or 2.5 +/- 0.4% BM and 7.1 +/- 2.7% deltaPV (VJ/400 m) in response to DD. CONCLUSIONS: Diuretic-induced dehydration was not detrimental to sprint and power performance. Metabolic, thermoregulatory, and cardiovascular variables were not significantly altered by DD. Furthermore, the theoretical benefit of dehydration on performance (i.e., BM reduction) was not supported in this subject cohort.

Adult↗
PubMed1988

Intracellular magnesium deficiency and effect of oral magnesium on blood pressure and red cell sodium transport in diuretic-treated hypertensive patients.

The effects of magnesium supplementation were tested in 20 patients with essential hypertension receiving long-term thiazide diuretic treatment (Th group) and 21 age-matched untreated patients (EHT group). Intra-erythrocyte cations, water content and the ouabain-sensitive sodium efflux rate constant were measured. The Th group received magnesium supplementations as MgO (600 mg Mg/day) for 4 weeks. In the Th group intra-erythrocyte magnesium and the sodium efflux rate constant were lower and red cell sodium was higher than in the EHT group. During magnesium supplementation, there were significant decreases (p less than 0.01) in intra-erythrocyte sodium content and mean blood pressure, and increases (p less than 0.005) in red cell magnesium content and the sodium efflux rate constant. These effects of magnesium were more evident in 9 patients who were unresponsive to diuretic therapy, a definite reduction in mean blood pressure, from 104.8 +/- 2.7 mmHg to 94.4 +/- 2.2 mmHg (p less than 0.001), being observed. In the remaining 11 patients, however, blood pressure remained unchanged. The sodium efflux rate constant was positively correlated with red cell magnesium content and negatively correlated with sodium content (r = 0.61, p less than 0.005 and r = -0.57, p less than 0.01, respectively). These results indicate that long-term diuretic treatment may give rise to intracellular magnesium deficiency and a suppression of cell membrane active sodium transport. The results also suggest that oral magnesium may decrease intracellular sodium, possibly through the activation of Na-K-ATPase, which in turn may contribute to the reduction in blood pressure. Therefore, magnesium supplementation may be a worthwhile additional therapy for diuretics.

Administration, Oral↗
PubMed1984

Decreased renal excretion of uric acid following diuretic administration in rats.

In order to evaluate the cause of diuretic-induced hyperuricemia which has been well documented in clinical studies, clearance experiments were performed in rats using furosemide and trichlormethiazide . The net flux in the tubular transport of uric acid was reabsorptive, and the fractional excretion of uric acid responded sensitively to the transtubular transport inhibitors, sodium probenecid and pyrazinoic acid. When the hemoconcentration was induced by highly potent doses of test diuretics, the inulin clearance and the fractional excretion of uric acid clearly decreased. The contraction of body fluid produced by intraperitoneal administration of polyethylene glycol resulted in marked decrease of inulin clearance and fractional excretion of uric acid. The decrease of uric acid excretory capacity under the treatment with trichlormethiazide was completely corrected by saline loading. Moreover, no significant change was found in the pyrazinoic acid-suppressible fractional excretion of uric acid between the diuretic-treated rats and the control animals. These studies suggest that furosemide- and trichlormethiazide -induced changes in the renal handling of uric acid are mediated by the fluid volume contraction and that the decrease in fractional excretion of uric acid by test diuretics is the result of reabsorptive enhancement of uric acid.

Animals↗